Project Summery/Abstract Age-related disorders including non-alcoholic fatty liver disease (NAFLD) and diabetes have replaced infectious diseases as the leading cause of death in developed countries. There is a pressing need to identify novel molecular targets that could lead to better therapeutic and diagnostic strategies for the management of these diseases. Numerous studies have demonstrated that altered serine metabolism is linking to NAFLD. These observations raise the intriguing possibility that there may be a causal relationship between aberrant serine metabolism and the development of the disease. Our studies show that the expression of SHMT2, a serine catabolic enzyme, is significantly reduced in the livers of the rodent models fed with high fat diet, suggesting that hepatic serine catabolism is reduced in response to caloric excess. Serine catabolism produces important metabolic intermediates including one-carbon unit and glycine. Recently, we and others have reported that inactivation of SHMT2 leads to impaired mitochondrial respiration in mammalian cells. Mechanistically, we have further demonstrated that SHMT2-mediated serine catabolism supplies the one- carbon metabolite essential for the assembly of respiratory Complex I, the gatekeeper enzyme of the mitochondrial respiratory chain. In addition, we found that targeted deletion of SHMT2 resulted in significantly increased fat accumulation and decreased expression of key ?-oxidation genes in hepatic cell line. Given the significant impact of mitochondrial dysfunction on the etiology of a number of metabolic diseases including NAFLD, we propose a mechanistic model where decreased hepatic SHMT2 expression leads to impaired mitochondrial respiration and thus increased hepatic steatosis and insulin resistance in individuals with overnutrition during aging. The overarching goal of this project is to test this model and determine if there is a causal link between serine metabolism and NAFLD susceptibility. This will be accomplished by characterizing the metabolic effects of experimentally altered hepatic SHMT2 gene expression in lean and obese mice. These studies represent an initial effort to explore the novel and potentially important possibility that hepatic serine catabolism affects disease susceptibility, which if true, would identify SHMT2 as a potential target for therapeutic intervention for NAFLD and other age-related diseases.